ab-basic principle 2

8/12/2019 AB-Basic Principle 2

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Basic Principles

of Antimicrobial Therapy


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Penicillin became available in quantitiessufficient for clinical use in 1941.

After that, streptomycin, chloramphenicol,and tetracycline were discovered. Since then,numerous classes of antimicorabial agentshave been identified, and a lot of drugs areavailable for use today.Antimicrobials are among the mostcommonly used drugs.


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Selective toxicity of antimicrobial (AM)

Ability to kill invading m.o without harming hosts cells

Effective treatment in infectious disease

BUT it requires an appropriate concentration to attackthe m.o while tolerabled by the host


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Chemotheraphy : Drugs with selective toxicity against invading

parasites (virus, bacteria, protozoa, fungi andhelminth)

Antibiotics :

Substances produced by some microorganism(or by pharmaceutical chemists) that kill/inhibitthe growth of other microorganism (m.o)

= antimicrobial


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Fig 1. The relationship of Host-Drug-Pathogen in chemotherapy


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Molecular Basis of Chemotherapy

Chemotherapeutic drugs should be toxic for invadingm.o in the host

Selective toxicity depends on biochemical differences

between parasite host Biochemical reaction as potential targets:

Class I: glucose & other carbon source

Class II: energy and class I compound to make amino acid,nucleotides, etc Class III: small molecules are built into larger molecules,

e.g. proteins, nucleic acid, peptidoglycan


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Biochemical Reactions as Potential Targets

Class I: poor targets

Folate synthesis inhibited by sulfonamides Folate utilisation inhibited by folate antagonist Pyrimidine & purine analogues produce fraudulent

nucleotides

Class II: better targets

Peptidoglycan synthesis B-lactam Protein synthesis work though tRNA (T-S); mRNA (AMG) Nucleic acid synthesis work though DNA (quinolon,

rifampicin)

Class III: important targets


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Formed Structure of the Cell

Amphotericine, azole (antifungal)Plasma membraneaffected by:

Anticancer, antihelminthicsMicrotubule functiondisrupted by:

Antihelminthics increase Cl- permeability Pyrantel (antihelminthics) causing

paralysis

Muscle fibresaffected by:


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Identity of m.oand itssensitivity to AM

Where is site ofinfection?

How is the safetyof AM well use?

Any patientsfactors?

Availability?

What about costof th/?

We need information about:


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For C.I. P pts cant wait the result ofm.o identification [gram (+) / (-)] andDST

Immunocompromised patients When? Take the specimen for lab first!! choose broad spectrum administration: ivHow?


14/41Strategic for empiric therapy

Empiric therapy

Coverage by a combination ofantibiotics such as, clindamycin plus gentamicin , effective against gr ( ),

gr (-) and anaerobes, or a singlebroad spectrum antibiotic, such asimipenem cilastatin

If Grampositive

onlyIf Gram

negative only

If mixed

If anaerobic only

Receive culture reportwith sensitivities

Cont. gr (+) coverage.

discontinue gram (-) &anaerobic coverage

Cont. gr (-) coverage

Discontinue gr (+) andanaerobic coverage

Cont. anaerobic coverage

Discontinue gr (+) & (-)coverage

Continue therapyas initiated


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Renaldysfunction

Liverdysfunction

For AM excretedthrough kidney

toxicity adjustthe dosage

orchange thedrugs

Dont give drugsconcentrated/eliminated by the liver(macrolides, sulfa)

toxicity


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Poor perfusion

Exp: diabeticfoot with PAD

difficult totreat infection

Pregnancyand lactation

Some AM crossplacenta & excreted in

the breast milkteratogenic or riseproblems (toxicity)

Exp: pyrimetamin(for toxoplasma),

AMG

Age

Newborn:immaturation oforgans function

Children: deal withgrowth process

Geriatric pts :alteration organs

function


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Both drugs and patients factors B-lactam is least toxic compared to

other AM Pts factors: age, co -morbiditySafety

Consider the efficacy AND the cost In EMG case: efficacy is the mostimportant!

Feasibility !

Cost-benefit


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BUT, some AM is -statics for certain m.o while its -cidal toanother m.o (chloramphenicol)

Bactericidal:

kills the m.o decreases the amount of m.o

Bacteriostatic:

Only stop growth &replication of m.o

So, it limits the spread ofinfection

Wait for immune systemto solve the rest


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narrow

single/limited group ofm.o

exp. INH only form.TB

extended Gram (+), (-) exp; ampicillin

broad

Not only to gr (+), (-) But also to other m.o Exp. TS,

chloramphenicol


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Select if possible only single AMIt prevents: Superinfections emerge of drug resistance Minimize toxicity the cost

BUT sometimes wee need drug combination Synergism more effective (B-lactam + AMG) Wider coverage


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1. Hypersensitivity Ag-Ab complex reaction Mild (urticaria) severe (anaphylaxtic reaction)

Exp: penicillin

2. Direct toxicity Toxic directly to the cellular

Related to the plasma conc. Exp: AMG (nepfro & oto-toxicity)

3. Superinfection

Broad spectrum AM alter Normal flora OI


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Resistance to AB

a. Nature of m.o (exp: gr (-) m.o areresistant to vancomycin)

b. Acquired resistance Spontaneous mutation DNA transfer

If with max doseof AM (toleratedby the host)

the growth ofm.o is not halted.

inappropriate use of the drugs Why its happen?


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Can be spread

From bacteria bacteria (byplasmid)

From plasmid plasmid (bytransposons)

Plasmid:extrachromosomal

genetic element

Can replicateindependently,

Can carry genescoding forresistance to AB

Transposons:stretches of DNA

can betransported frompalsmid - another

Also from plasmidto chromosom &v.v

Resistance to AB


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Resistance to AB: Mechanism ?

Altered expression of proteins in DR-organismModification of target sites MRSA, quinolon resistance

Decreased accumulation Decrease permeability OR

increase Efflux system that pumpout the drug

Enzymatic inactivation B-lactamase

Genetic alterations DR

Spontaneous mutation of DNA DNA transfer of DR (through plasmid)


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Multidrug Resistance (MDR)

Resistance to commonly used ABMDR-TB (resistant to > 2 anti-TB drugs)

Some strains of Staph. & enterococc. (resistant to most all AB)

Lead to serious untreatable infection


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B-lactams AM (B-lactam ring): 1 st , 2nd , 3rd, 4 th generation AMG : AMK, KNM, STREPT

a. Chemical structure

Anti viral Antifungal Antibacterial !!!

b. Activity against certain m.o

Inhibitors of metabolism Inhibitors of cell wall synthesis Inhibitors of protein synthesis

Inhibitors of nucleic acid fct/synthesis

c. Mechanism of action


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ab-basic principle 2

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